Recombinant human insulin-like growth factor I, recombinant human growth hormone, and sex steroids: effects on markers of bone turnover in humans.

Sex steroids, GH, and insulin-like growth factor I (IGF-I) have all been shown to be highly anabolic in bone. Using available markers of bone formation, we measured the changes in serum concentrations of carboxy-terminal propeptide of type I collagen (PICP) and osteocalcin in five groups of subjects given different bone anabolic hormones: group I (five males and three females; mean +/- SE age, 25 +/- 2 yr) received recombinant human IGF-I (rhIGF-I) as a constant 28-h infusion i.v. (5-10 micrograms/kg.h); group II (three males and two females; 25 +/- 2 yr) received rhIGF-I (100 micrograms/kg, sc, twice daily) for 5-7 days; group III (five males; 28 +/- 2 yr) received rhGH (0.025 mg/kg.day, sc, for 7 days, alone (group IIIa) or followed by a 28-h sc infusion of rhIGF-I (10 micrograms/kg.h) in addition to rhGH (group IIIb); group IV (six prepubertal boys; 13 +/- 0.6 yr) received testosterone enanthate (100 mg, im) twice over 4 weeks; and group V (five hypogonadal girls with Turner's syndrome) received different forms of estrogen for 4 weeks. Most groups (except for III) had deoxypyridinoline concentrations (a marker of bone resorption) measured in urine as well. Each subject served as his/her own control. rhIGF-I treated subjects in group I showed a marked decrease in circulating PICP concentrations after 4 h of infusion (from 116.8 +/- 19.2 micrograms/L to 89.6 +/- 16.3; P < 0.01), followed by a marked increase at 28 h (137.6 +/- 19.7; P < 0.01) and a sustained increase 5-7 days after sc therapy (group II). This decrease followed by an increase in PICP concentrations after rhIGF-I may be secondary to the marked suppression of circulating insulin observed at 4 h followed by the establishment of an insulin-like effect of the peptide. Subjects receiving rhGH alone (group IIIa) also had comparable increases in circulating PICP (from 107.6 +/- 8.7 to 125.0 +/- 10.9; P < 0.01) and a further additive increase when rhIGF-I was coadministered (140.9 +/- 10.3; P < 0.01). These changes were accompanied by comparable increases in IGF-I concentrations in all groups (I, II, and III). Hypogonadal children had higher levels of circulating PICP than adults and showed the most significant increases after therapy [group IV, 212.2 +/- 13.8 to 429.9 +/- 52.4 micrograms/L (P < 0.001); group V, 312.8 +/- 49.0 to 355.5 +/- 44.3 (P < 0.04)]. The latter was observed despite either a modest (group IV) or no increase (group V) in circulating IGF-I concentrations. None of the groups studied showed any change in serum osteocalcin concentrations after treatment. Urinary deoxypridinoline concentrations also increased after rhIGF-I and testosterone administration. We conclude that rhIGF-I, rhGH, and sex steroid hormones all markedly increase measures of bone turnover, and that rhIGF-I and rhGH can synergize on this effect on bone. These data collectively suggest that IGF-I and sex steroid hormones (testosterone and estrogen) can impact bone formation independently, and that the actions of IGF-I, GH, sex steroid hormones (and perhaps insulin) may synergize to maximally stimulate attainment of peak bone mass in humans. PICP measurement appears to be a sensitive marker of short term anabolic hormone actions in bone.